Identification of cyclic peptides able to mimic the functional epitope of IgG1-Fc for human Fc gammaRI.
Identification of short, structured peptides able to mimic potently protein-protein interfaces remains a challenge in drug discovery. We report here the use of a naive cyclic peptide phage display library to identify peptide ligands able to recognize and mimic IgG1-Fc functions with Fc gammaRI. Selection by competing off binders to Fc gammaRI with IgG1 allowed the isolation of a family of peptides sharing the common consensus sequence TX(2)CXXthetaPXLLGCPhiXE (theta represents a hydrophobic residue, Phi is usually an acidic residue, and X is any residue) and able to inhibit IgG1 binding to Fc gammaRI. In soluble form, these peptides antagonize superoxide generation mediated by IgG1. In complexed form, they trigger phagocytosis and a superoxide burst. Unlike IgG, these peptides are strictly Fc gammaRI-specific among the Fc gammaRs. Molecular modeling studies suggest that these peptides can adopt 2 distinct and complementary conformers, each able to mimic the discontinuous interface contacts constituted by the Cgamma2-A and -B chains of Fc for Fc gammaRI. In addition, by covalent homodimerization, we engineered a synthetic bivalent 37-mer peptide that retains the ability to trigger effector functions. We demonstrate here that it is feasible to maintain IgG-Fc function within a small structured peptide. These peptides represent a new format for modulation of effector functions.
Bonetto
Stephane
S
MedImmune, Research, Granta Park, Milstein Bldg., Cambridge, CB21 6GH, UK.
Spadola
Loredana
L
Buchanan
Andrew G
AG
Jermutus
Lutz
L
Lund
John
J
D000595:Amino Acid Sequence; D040761:Biomimetic Materials / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D030562:Databases, Protein; D000939:Epitopes / Q000276:immunology*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology* / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology* / Q000378:metabolism; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects; D011485:Protein Binding; D055503:Protein Multimerization; D017452:Receptors, IgG / Q000276:immunology* / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D000939:Epitopes; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D010456:Peptides, Cyclic; D017452:Receptors, IgG; D013481:Superoxides